Medical devices with selective titanium oxide coatings

ABSTRACT

Medical devices, such as endoprostheses, and methods of making the devices are described. In some embodiments, a medical device includes a body of interconnected bands and connectors forming an elongated tubular structure having an inner luminal wall surface and an outer abluminal wall surface and defining a central lumen or passageway. The inner luminal wall surface and side wall surface of the bands and connectors forming transverse passageways through the elongated tubular structure can bear a coating of hydrophilic material and the outer abluminal wall surface of the tubular structure can bear a coating of hydrophobic material.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 60/818,101, filed on Jun. 29, 2006. The contents of U.S. ApplicationSer. No. 60/818,101 are incorporated by reference as part of thisapplication.

TECHNICAL FIELD

This invention relates to medical devices, such as endoprostheses (e.g.,stents).

BACKGROUND

The body defines various passageways such as arteries, other bloodvessels, and other body lumens. These passageways sometimes becomeoccluded or weakened. For example, the passageways can be occluded by atumor, restricted by a plaque, or weakened by an aneurysm. When thisoccurs, the passageway can be reopened or reinforced, or even replaced,with a medical endoprosthesis. An endoprosthesis is typically a tubularmember that is placed in a lumen in the body. Examples of endoprosthesesinclude stents, covered stents, and stent-grafts.

Endoprostheses can be delivered inside the body by a catheter thatsupports the endoprosthesis in a compacted or reduced-size form as theendoprosthesis is transported to a desired site. Upon reaching the site,the endoprosthesis is expanded, for example, or allowed to expand, sothat it can contact the walls of the lumen.

Endoprostheses can be coated with biocompatible materials and/orbiomolecules, including active pharmaceutical agents.

SUMMARY

The disclosure relates to medical devices, such as endoprostheses. Theinvention is based, inter alia, on the discovery that coatingendoprostheses, e.g., stents, with hydrophilic and/or hydrophobicmaterial(s) allows for generation of complex biomolecule coatingpatterns on the endoprostheses.

In one aspect, the disclosure features a medical device having a body ofinterconnected bands and connectors forming an elongated tubularstructure having an inner luminal wall surface and an outer abluminalwall surface and defining a central lumen or passageway, wherein theinner luminal wall surface and side wall surface of the bands andconnectors forming transverse passageways through the elongated tubularstructure bear a coating of hydrophilic material and the outer abluminalwall surface of the tubular structure bears a coating of hydrophobicmaterial.

Embodiments may include one or more of the following features.

At least one or more selected regions of the luminal and side wallsurfaces of the medical device can bear a coating of hydrophilicmaterial, e.g., superhydrophilic material, or the entire luminal andside wall surfaces of the medical device can bear a coating ofhydrophilic material, e.g., superhydrophilic material. At least one ormore selected regions of the abluminal surface of the medical device canbear a coating of hydrophobic material or the entire abluminal wallsurface of the medical device can bear a coating of hydrophobicmaterial.

The coating of the luminal, side and abluminal wall surfaces can includetitanium (+y) oxide (−x) (Ti_(x)O_(y)) e.g., titanium dioxide. Titanium(+y) oxide (−x) can have a crystalline structure, e.g., be in an anataseor rutile phase. Titanium (+y) oxide (−x) can be in an amorphous phase.Titanium (+y) oxide (−x) can be in an anatase phase combined with atleast one of the following phases: rutile, brookite, monoclinic,amorphous, titanium (+y) oxide (−x) (II), and titanium (+y) oxide (−x)(H). Titanium (+y) oxide (−x) can be nano-porous, e.g., meso-porous ormicro-porous. Titanium (+y) oxide (−x) can be generally smooth, i.e.,not nano-porous. In addition to the titanium (+y) oxide (−x), thecoating can include phosphorus, e.g., up to 5% of phosphorus by weight.In addition to the titanium (+y) oxide (−x) and/or phosphorus, thecoating can include iridium oxide or ruthenium oxide or both. Titanium(+y) oxide (−x) can be doped with at least one of the followingelements: iron, carbon, nitrogen, bismuth and vanadium, e.g., it can bedoped with both bismuth and vanadium. A layer of organic compound, e.g.,alkyl silane, aryl silane and/or fluoroalkyl silane, can be depositedover the titanium dioxide coating. Specific examples of organiccompounds that can be deposited over the coating include octadecylsilaneand octadecylphosphonic acid.

The coating upon the abluminal wall surface can also includebiomolecules, e.g., paclitaxel, and a polymer, e.g.,poly(styrene-b-isobutylene-b-styrene). The coating upon the abluminalwall surface can also include an organic solvent or a hydrophobic lipidcapsule. The coating upon the abluminal wall surface, e.g., titanium(+y) oxide (−x) coating with biomolecules, e.g., titanium dioxidecoating with biomolecules, can include a second layer of titanium (+y)oxide (−x), e.g., titanium dioxide.

The coating upon the luminal and side wall surfaces can also includebiomolecules, e.g., heparin.

The coating upon the abluminal, luminal and side wall surfaces caninclude biomolecules. Biomolecules of the abluminal wall surface coatingcan be of a type different from biomolecules of the luminal and sidewall surfaces coating.

In another aspect, the disclosure features a medical device having abody of interconnected bands and connectors forming an elongated tubularstructure having an inner luminal wall surface and an outer abluminalwall surface and defining a central lumen or passageway, wherein theinner luminal wall surface and side wall surface of the bands andconnectors forming transverse passageways through the elongated tubularstructure bear a coating of hydrophobic material and the outer abluminalwall surface of the tubular structure bears a coating of hydrophilicmaterial.

Embodiments may include one or more of the following features.

At least one or more selected regions of the luminal and side wallsurfaces of the medical device can bear a coating of hydrophobicmaterial or the entire luminal and side wall surfaces of the medicaldevice can bear a coating of hydrophobic material. At least one or moreselected regions of the abluminal surface of the medical device can beara coating of hydrophilic material, e.g., superhydrophilic material, orthe entire abluminal wall surface of the medical device can bear acoating of hydrophilic material, e.g., superhydrophilic material.

The coating of the luminal, side and abluminal wall surfaces can includetitanium (+y) oxide (−x), e.g., titanium dioxide. Titanium (+y) oxide(−x) can have a crystalline structure, e.g., be in an anatase or rutilephase. Titanium (+y) oxide (−x) can be in an amorphous phase. Titanium(+y) oxide (−x) can be in an anatase phase combined with at least one ofthe following phases: rutile, brookite, monoclinic, amorphous, titanium(+y) oxide (−x) (II), and titanium (+y) oxide (−x) (H). Titanium (+y)oxide (−x) can be nano-porous, e.g., meso-porous or micro-porous.Titanium (+y) oxide (−x) can be generally smooth, i.e., not nano-porous.In addition to the titanium (+y) oxide (−x), the coating can includephosphorus, e.g., up to 5% of phosphorus by weight. In addition to thetitanium (+y) oxide (−x) and/or phosphorus, the coating can includeiridium oxide or ruthenium oxide or both. Titanium (+y) oxide (−x) canbe doped with at least one of the following elements: iron, carbon,nitrogen, bismuth and vanadium, e.g., it can be doped with both bismuthand vanadium. A layer of organic compound, e.g., alkyl silane, arylsilane and/or fluoroalkyl silane, can be deposited over the titanium(+y) oxide (−x) coating. Specific examples of organic compounds that canbe deposited over the coating include octadecylsilane andoctadecylphosphonic acid.

The coating upon the abluminal wall surface can also includebiomolecules. The coating upon the abluminal wall surface, e.g.,titanium (+y) oxide (−x) coating with biomolecules, e.g., titaniumdioxide coating with biomolecules, can include a second layer oftitanium (+y) oxide (−x), e.g., titanium dioxide.

The coating upon the luminal and side wall surfaces can also includebiomolecules. The coating, e.g., including biomolecules, can alsoinclude a polymer, e.g., poly(styrene-b-isobutylene-b-styrene). Thecoating upon the luminal and side wall surfaces can also include anorganic solvent or a hydrophobic lipid capsule. The coating upon theluminal and side wall surfaces, e.g., titanium (+y) oxide (−x) coatingwith biomolecules, e.g., titanium dioxide coating with biomolecules, caninclude a second layer of titanium (+y) oxide (−x), e.g., titaniumdioxide.

The coating upon the abluminal, luminal and side wall surfaces caninclude biomolecules. Biomolecules of the abluminal wall surface coatingcan be of a different type than the biomolecules on the luminal and sidewall surfaces coating.

In another aspect, the disclosure features a method of producing amedical device, the method having the following steps:

(i) coating wall surfaces of a medical device having a body ofinterconnected bands and connectors forming an elongated tubularstructure having an inner luminal wall surface and an outer abluminalwall surface and defining a central lumen or passageway, wherein theinner luminal wall surface and side wall surface of the bands andconnectors form transverse passageways through the elongated tubularstructure with hydrophilic titanium (+y) oxide (−x), e.g., titaniumdioxide;

(ii) exposing the medical device to conditions sufficient to cause thetitanium (+y) oxide (−x) coating to become hydrophobic;

(iii) exposing selected surfaces of the medical device to conditionssufficient to cause the titanium (+y) oxide (−x) coating to becomesuperhydrophilic; and

(iv) coating the medical device in a first solution compatible withdesired biomolecules.

Embodiments may include one or more of the following features.

The first solution can be non-polar or polar. The first solution caninclude a desired biomolecule, e.g., paclitaxel or heparin. The firstsolution can also include a polymer, e.g.,poly(styrene-b-isobutylene-b-styrene). The first solution can include ahydrophobic lipid capsule.

The first solution can include at least one polar solvent configured toadhere to the hydrophilic surfaces of the medical device and at leastone non-polar solvent configured to adhere to the hydrophobic surfacesof the medical device. The solution can include at least one biomoleculecompatible with at least one solvent, e.g., a first biomoleculecompatible with the polar solvent and a second biomolecule compatiblewith the non-polar solvent. The first biomolecule can be heparin and thesecond biomolecule can be paclitaxel. The first solution can furthercomprise a polymer, e.g., poly(styrene-b-isobutylene-b-styrene). Thefirst solution can include hydrophobic lipid capsules containingbiomolecules, as well as hydrophilic groups.

The method can have a further step of coating the medical device in asecond solution compatible with desired biomolecules. The secondsolution can be non-polar or polar. The second solution can includebiomolecules, e.g., paclitaxel or heparin. The second solution caninclude a polymer. The second solution can include a hydrophobic lipidcapsule.

The method can include a further step of coating the medical device ofstep (i) with a layer of organic compound, e.g., alkyl silane, arylsilane and/or fluoroalkyl silane, specifically, octadecylsilane oroctadecylphosphonic acid.

The conditions of step (ii) can include placing the medical device inthe dark and/or wet-rubbing. The conditions of step (iii) can includeilluminating surfaces of the medical device that bear the coating withultraviolet light. At least a region of the luminal and side wallsurfaces that bear the coating can be illuminated. At least a region ofthe abluminal wall surface that bears the coating can be illuminated.Step (iii) can also include exposing at least a region of the surfacesthat have become superhydrophilic to conditions sufficient for thesurface region to become hydrophobic, e.g., by wet-rubbing or by placingthe medical device in the dark.

The coating process of step (iv) can be dipcoating, gas-assistedspraying, electrostatic spraying, electrospinning and/or roll-coating.

The titanium (+y) oxide (−x) coating can be titanium dioxide coating.The coating can have a crystalline structure, e.g., be in a rutile oranatase phase. Titanium (+y) oxide (−x) can be in an amorphous phase.Titanium (+y) oxide (−x) can be in an anatase phase combined with atleast one of the following phases: rutile, brookite, monoclinic,amorphous, titanium (+y) oxide (−x) (II), and titanium (+y) oxide (−x)(H). Titanium (+y) oxide (−x) can be nano-porous, e.g., meso- ormicro-porous. Titanium (+y) oxide (−x) can be generally smooth, i.e.,not nano-porous. In addition to the titanium dioxide, the coating caninclude phosphorus, e.g., up to 5% of phosphorus by weight. In additionto the titanium (+y) oxide (−x) and/or phosphorus, the coating caninclude iridium oxide or ruthenium oxide or both. Titanium (+y) oxide(−x) can be doped with at least one of the following elements: iron,carbon, nitrogen, bismuth and vanadium, e.g., it can be doped with bothbismuth and vanadium. A layer of organic compound, e.g., alkyl silane,aryl silane and/or fluoroalkyl silane, can be deposited over thetitanium (+y) oxide (−x) coating. Specific examples of organic compoundsthat can be deposited over the coating include octadecylsilane andoctadecylphosphonic acid.

The instant disclosure provides stents with various patterns ofhydrophobic and hydrophilic coating. These coating patterns allowplacement of various biomolecules on various regions of a stentresulting in complex biomolecule patterns on stents. The disclosure alsoprovides methods of generating stents with such complex coating and/orbiomolecule patterns.

The term “biomolecule” as used herein refers to chemical compounds,therapeutic agents, drugs, pharmaceutical compositions and similarsubstances that exert biological effects.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present disclosure, suitable methods andmaterials are described below. All publications, patent applications,patents, and other references mentioned herein are incorporated byreference in their entirety. In case of conflict, the presentspecification, including definitions, will control. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting. Other features and advantages of the disclosure will beapparent from the following detailed description, and from the claims.

DESCRIPTION OF DRAWINGS

FIG. 1A is a perspective view of a stent.

FIG. 1B is a cross-section of a wall of the stent taken along the linesA1-A1.

FIG. 2 is a flow chart of an embodiment of a method of selectivelycoating the stent.

FIG. 3A is a cross-section of a wall of the stent of FIG. 1A, takenalong the lines A1-A1.

FIG. 3B is a cross-section of a wall of the stent of FIG. 1A, takenalong the lines A1-A1.

FIG. 4 is a flow chart of another embodiment of a method of selectivelycoating the stent.

DETAILED DESCRIPTION

Referring to FIG. 1A, stent 10 having a body of interconnected bands 12and connectors 11 forming an elongated tubular structure is shown.Referring to FIG. 1B, the cross-section of the body of stent 10 showsthat the stent has an inner luminal surface 13, side wall surface 14 andan outer abluminal surface 15. The surfaces 13, 14 and 15 bear a coating16 of titanium (+y) oxide (−x) (Ti_(x)O_(y)) e.g., titanium dioxide(TiO₂). Coating 16 of luminal surface 13 and side wall surface 14further includes biomolecules 17. Coating 16 of abluminal surface 15further includes biomolecules 18.

Stent 10 can be produced in a variety of ways. For example, referring toFIG. 2, a method 20 of producing stent 10 with selectively coatedsurfaces is described. Stent 10 is generated (step 21). Surfaces 13, 14and 15 of stent 10 are coated with Ti_(x)O_(y) (step 22), e.g.,hydrophilic Ti_(x)O_(y), e.g., superhydrophilic Ti_(x)O_(y), e.g.,superhydrophilic TiO₂, resulting in coating 16. Stent 10 is then beexposed to conditions sufficient to cause the Ti_(x)O_(y) coating 16 tobecome hydrophobic (step 23), e.g., by placing stent 10 in a darkenvironment for a couple of days or by a process called “wet-rubbing”(see, e.g., Kamei et al., Surf. Science 463:L609-12, 2000), in which asuperhydrophilic surface is turned to a hydrophobic surface by removalof the surface hydroxyl groups.

Selected surfaces of stent 10 are then exposed to conditions sufficientto cause coating 16 of the selected surfaces to become hydrophilic,e.g., superhydrophilic (step 24), e.g., by exposure to ultravioletlight. For example, referring to FIG. 3A, a source of ultraviolet light30 can be placed generally on the luminal side of stent 10, e.g., insidestent 10. Light source 30 illuminates luminal surface 13 and side wallsurface 14 bearing Ti_(x)O_(y) coating 16. Such illumination will causecoating 16 to become superhydrophilic. While light source 30 illuminatessurfaces 13 and 14, abluminal surface 15 bearing coating 16 is blockedfrom exposure, e.g., with a mandrel. Thus, after sufficientillumination, the resulting stent 10 bears coating 16 that issuperhydrophilic on luminal surface 13 and side walls surface 14, andhydrophobic on abluminal surface 15.

In another embodiment, illustrated in FIG. 3B, a source of ultravioletlight 30 can be placed generally on the abluminal side of stent 10.Light source 30 illuminates the abluminal surface 15 that bears coating16 of Ti_(x)O_(y). While light source 30 illuminates surface 15,surfaces 13 and 14 are blocked. Thus, after sufficient illumination, theresulting stent 10 bears coating 16 that is hydrophilic on abluminalsurface 15 and hydrophobic on luminal surface 13 and side surface 14.

Both the light exposure, e.g., ultraviolet light exposure, andwet-rubbing can be carried out on a selective micro-scale, vastlyexpanding the range of hydrophilic and hydrophobic regions of stent 10that can be realized. Other patterns, in addition to the ones describedabove can be realized. For example, coating 16 of both luminal surface13 and abluminal surface 15 can be turned hydrophilic with selectivelight exposure. In another example, only portions of coating 16 of anyof the surfaces 13, 14 and/or 15 may be turned hydrophilic. The possiblepatterns are numerous.

Further referring to FIG. 2, stent 10 bearing coating 16 that isselectively hydrophilic and hydrophobic is then coated, e.g., bydipcoating, gas-assisted spraying, electrostatic spraying,electrospinning, or roll-coating, in desired substances compatible withdesired biomolecules 17 and 18 (step 25). For example, stent 10 can becoated, e.g., dipped in a non-polar solution containing a biomolecule,e.g., paclitaxel in Xylene (e.g., up to 1% by weight of paclitaxel) andoptionally a polymer, e.g., poly(styrene-b-isobutylene-b-styrene)(SIBS). Non-polar solution and biomolecule adhere to non-illuminatedsurfaces bearing hydrophobic coating 16. The stent can be dried and theprocess repeated, building layers upon the hydrophobic surfaces. Inanother embodiment, stent 10 can be further coated, e.g., dipped in apolar solution containing another biomolecule, e.g., heparin. The polarsolution will adhere to illuminated surfaces bearing hydrophilic coating16. In yet another embodiment, stent 10 can be coated, e.g., bydipcoating, gas-assisted spraying, electrostatic spraying,electrospinning, or roll coating, in a solution that includes acombination of both polar and non-polar solvents with respectivelydissolved biomolecules and, optionally, polymers. In this embodiment,the polar solvent will adhere to the hydrophilic regions of stent 10,while the non-polar solvent will adhere to the hydrophobic regions ofstent 10. The resulting stent 10 will have surfaces selectively coatedwith multiple biomolecules.

Thus, in one embodiment, stent 10 bears coating 16 of hydrophilicTi_(x)O_(y). Stent 10 is left in the dark for a time sufficient forcoating 16 to become hydrophobic. Next, luminal surface 13 and side wallsurface 14 are illuminated with UV light source 30, turning themsuperhydrophilic. Such luminal surface 13 and side wall surface 14bearing hydrophilic coating 16 are coated with polar solutions andbiomolecules, e.g., heparin. The abluminal wall surface 15 bearinghydrophobic coating 16, on the other hand, is coated with non-polarsolutions and biomolecules, e.g., paclitaxel, e.g., paclitaxel andbinder polymer, e.g., SIBS. In one embodiment, stent 10 can be coatedwith a solution that includes a combination of both polar and non-polarsolvents with respectively dissolved biomolecules and, optionally,polymers.

In another embodiment, stent 10 bears coating 16 of hydrophilicTi_(x)O_(y). Stent 10 is left in the dark for a time sufficient for itto become hydrophobic. Next, abluminal wall surface 15 bearing coating16 is illuminated with UV light source 30, turning it superhydrophilic.Luminal surface 13 and side wall surface 14 bearing coating 16 arecoated with non-polar solutions and biomolecules. The abluminal surface15 is coated with polar solutions and biomolecules. In one embodiment,stent 10 can be coated with a solution that includes a combination ofboth polar and non-polar solvents with respectively dissolved drugs and,optionally, polymers.

As discussed supra, in another embodiment, rather than illuminating theentire luminal surface 13 and side wall surface 14 bearing coating 16 orthe entire abluminal surface 15 (in step 24 of FIG. 2), selected regionsof any of surfaces 13, 14 and 15 may be illuminated, and selectedregions may be coated in desired polar and non-polar solutions. Anynumber and variation of coating patterns is possible.

Referring to FIG. 4, another method of generating a selectively coatedstent 10 is illustrated. Stent 10 is generated (step 41). Surfaces 13,14 and 15 of stent 10 are coated with Ti_(x)O_(y) (step 42), e.g.,hydrophilic Ti_(x)O_(y), e.g., superhydrophilic Ti_(x)O_(y), e.g.,superhydrophilic TiO₂, resulting in coating 16. Stent 10 is then exposedto conditions sufficient to cause the Ti_(x)O_(y) coating 16 to becomehydrophobic (step 43), e.g., by placing stent 10 in a dark environmentfor a few days. Surfaces 13, 14 and/or 15 or selected portions ofsurfaces 13, 14 and 15 of stent 10 bearing coating 16 are then exposedto conditions sufficient to cause the coating 16 to become hydrophilic,e.g., superhydrophilic, e.g., by UV illumination (e.g., XE lamp, 20minutes exposure time) (step 44). Selected surfaces exposed to UVillumination can include the entire surfaces 13, 14 and 15 bearingcoating 16. Selected surfaces that have been exposed to UV illuminationare subsequently exposed to conditions sufficient to cause coating 16 tobecome hydrophobic (step 45). The conditions can include wet-rubbingselected surfaces, e.g., luminal and abluminal surfaces, or any othercombination of surfaces, with either a glass, a steel or a paper surface(see, e.g., Kamei et al.). Again, both the wet-rubbing and the UVexposure can be done on a selective micro-scale, vastly expanding therange of patterns of hydrophobic and hydrophilic regions that can berealized.

Further referring to FIG. 4, stent 10 is coated, e.g., by dipcoating,gas-assisted spraying, electrostatic spraying, electrospinning orroll-coating, in desired substance(s) (step 46). One interestingapplication of wet-rubbing is that it allows just the surface to beturned from a hydrophilic porous Ti_(x)O_(y) coating into a hydrophobicsurface, while leaving the buried (underlying) porous structurehydrophilic. This can enable coating stent 10 with various combinationsof polar and non-polar solvents with different dissolved drugs and/orpolymers to create contrasting coating composition from top to bottominside of the porous Ti_(x)O_(y) coating. In one embodiment, stent 10can be coated, e.g., by dipcoating, gas-assisted spraying, electrostaticspraying, electrospinning or roll-coating, in a non-polar solutioncontaining biomolecules, e.g., paclitaxel, e.g., paclitaxel and binderpolymer, e.g., SIBS, and in a polar solution containing biomolecules,e.g., heparin, e.g., heparin and polymer. In another embodiment, stent10 can be coated, e.g., by dipcoating, gas-assisted spraying,electrostatic spraying, electrospinning or roll-coating, in a solutionthat includes a combination of both polar and non-polar solvents withrespectively dissolved biomolecules, e.g., drugs, and, optionally,polymers.

In another embodiment, once stent 10 has been coated with desiredbiomolecules and/or polymers, a second porous coating of Ti_(x)O_(y) canbe applied. In this embodiment, Ti_(x)O_(y) can be applied without theuse of high-temperature step. Ti_(x)O_(y) can be applied, e.g., viamicrowave-assisted deposition. In this embodiment, biomolecules on thestent, e.g., paclitaxel, can diffuse through the pores of the secondTi_(x)O_(y) layer.

In another embodiment, hydrophilic biomolecules can be packaged intohydrophobic lipid capsules (e.g., liposomes) and applied to hydrophobiccoating 16.

Further referring to FIG. 4, step 42 of method 40 can include coatingselected regions stent 10 with Ti_(x)O_(y) that is nano-porous, e.g.,meso-porous or micro-porous, and other selected regions with Ti_(x)O_(y)that is generally smooth, i.e., not nano-porous. In one embodiment, theregions coated with nano-porous coating can be luminal and side wallsurfaces 13 and 14, while the regions with smooth coating can beabluminal wall surfaces 15. In another embodiment, the regions withnano-porous coating can be abluminal wall surfaces 15, while the regionswith smooth coating can be luminal and side wall surfaces 13 and 14.Entire stent 10 coated with nano-porous and smooth Ti_(x)O_(y) can thenbe exposed to conditions sufficient for coating 16 to becomesuperhydrophilic, e.g., by UV irradiation (step 44). Entire stent 10 canthen be exposed to conditions sufficient to cause selected regions ofcoating 16 to become hydrophobic, e.g., by placing stent 10 in darkconditions for a certain timeframe, e.g., a number of days or weeks(step 45). In step 45, the regions coated with nano-porous Ti_(x)O_(y)will remain superhydrophilic (see, e.g., Gu, App. Phys. Lett.85(21):5067-69, 2004), while the regions coated with smooth Ti_(x)O_(y)will become hydrophobic. The resulting stent 10 can be coated e.g., bydipcoating, gas-assisted spraying, electrostatic spraying,electrospinning or roll-coating, in desired substance(s) (step 46).Stent 10 can be coated with polar solutions, non-polar solutions orsolutions containing a combination of polar and non-polar solvents,containing compatible biomolecules and/or polymers, as discussed above.

In use, stent 10 can be used, e.g., delivered, using a catheter deliverysystem. Catheter systems are described, e.g., in Wang U.S. Pat. No.5,195,969, Hamlin U.S. Pat. No. 5,270,086, and Raeder-Devens U.S. Pat.No. 6,726,712. Stents and stent delivery are also exemplified by theRadius® or Symbiot® systems, available from Boston Scientific Scimed,Maple Grove, Minn. Stent 10 bearing more than one type of a biomolecule,e.g., biomolecules 17 and 18, can deliver the biomolecules to, e.g., ablood vessel. Biomolecules 17 and 18 can target various cells of theblood vessels, e.g., endothelial cells or smooth muscle cells.

As discussed, coating 16 of stent 10 can include Ti_(x)O_(y),preferably, titanium dioxide. Titanium dioxide, also known as titanium(IV) oxide or titania is the naturally occurring oxide of titanium,chemical formula TiO₂. TiO₂ occurs in a number of forms: rutile,anatase, brookite, titanium dioxide (B) (monoclinic), titanium dioxide(II), and titanium dioxide (H). Carp et al., Prog. Solid State Chem.32:33-177, 2004. TiO₂ coatings are known to be blood-compatible. Maitzet al., Boston Scientific Corporation internal report, 2001; Tsyganov etal., Surf. Coat. Tech. 200:1041-44, 2005. Blood-compatible substancesshow only minor induction of blood clot formation. TiO₂ in both rutileand anatase phases shows low platelet adhesion. Implantation ofphosphorus in the top surface of the rutile phase (e.g., at an iondensity of about 2% to about 5%) decreases platelet adhesion to TiO₂.Maitz et al.

Morphology, crystal structure and doping of Ti_(x)O_(y) coating 16 aresome elements that need to be taken into account when making and usingstent 10. Ti_(x)O_(y) coating 16 of stent 10 can be a crystal (anataseor rutile structure). Crystal structure is photoactive. Crystalstructure also has porosity or roughness that facilitates adhesion andstorage of biomolecules 17 and 18, that can be placed on coating 16alone or in combination with polymers and/or other biomolecules. Coating16 can also be amorphous (Karuppuchamy et al., Vacuum 80:494-98, 2006)or be a combination of one or more of the following phases: anatase,rutile, brookite, amorphous, monoclinic, titanium (+y) oxide (−x) (II)and/or titanium (+y) oxide (−x) (H).

Instead of using pure Ti_(x)O_(y) for coating, phosphorus can beembedded at a low percentage (e.g., about 0.5 to about 5%) into theTi_(x)O_(y) layer (e.g., using plasma immersion process) to increaseblood compatibility of the coating. Maitz et al.

In other embodiments, coating 16 can be a combination of Ti_(x)O_(y) andiridium oxide (IrOx); or a combination of Ti_(x)O_(y) and rutheniumoxide (RuOx); or a combination of Ti_(x)O_(y), IrOx and RuOx. RuOx andIrOx can decrease any potential inflammation ongoing in the cellssurrounding stent 10 in the body, because these compounds can catalyzebreakdown of by-products of stressed cells.

In one embodiment, Ti_(x)O_(y) coating 16 can be doped, e.g., with iron(Fe), carbon (C), nitrogen (N), bismuth (Bi), vanadium (V) or theircombination. Fe-doping enhances Ti_(x)O_(y) conversion rate ofphotoinduced hydrophilicity and reduces the rate of conversion fromhydrophilic to hydrophobic state. Yu et al., Mat. Chem. Phys. 95:193-96,2006. Bi- and/or V-doping can decrease the water contact angle, whileBi-V-doping can enhance maintenance of a low water contact angle underdark conditions. Hong et al., Mat. Lett. 60:1296-1305, 2006. C-dopinghas also been reported to influence hydrophilic properties of TiO₂. Irieet al, Thin Solid Films 510:21-5, 2006.

A number of techniques can be used to deposit Ti_(x)O_(y) coating 16 onstent 10, including sol-gel routes and cathodic electrodeposition.Karuppuchamy et al., Solid State Ionics 151:19-27, 2002; Karuppuchamy etal., Mat. Chem. Phys. 93:251-54, 2005; Hattori et al., Langmuir15:5422-25, 1999. Many deposition techniques utilize a high-temperatureprocessing step (e.g., heating to about 400° C.) to turn deposited filminto crystal structure. If such a high-temperature step is undesirable(e.g., if the stent already has a coating of thermo-sensitive elements,such as certain polymers, microelectromechanical systems (MEMs), orbiomolecules), microwave-assisted deposition of Ti_(x)O_(y) can be used.Vigil et al., Langmuir 17:891-96, 2001, Gressel-Michel et al., J. Coll.Interf. Science 285:674-79, 2005. In one method of microwave-assisteddeposition, anatase particles are synthesized directly in suspensionusing a microwave reactor and the particles (of about 70 nm in diameter)are deposited by a dipcoat process at room temperature. Gressel-Michelet al. Chemical bath deposition is another method that avoids ahigh-temperature step in Ti_(x)O_(y) deposition. Pathan et al., App.Surf. Science 246:72-76, 2005.

As mentioned above, hydrophilic Ti_(x)O_(y) coating 16 will turnhydrophobic when left in the dark. Yu et al.; Karuppuchamy et al., 2005.Ti_(x)O_(y) coatings, however, are known to switch from hydrophobic tosuperhydrophilic when exposed to ultraviolet (UV) light illumination.This effect exists not only in the anatase and rutile phases (Yu etal.), but also in the amorphous phase (Karuppuchamy et al, Vacuum80:494-98, 2006). Ti_(x)O_(y) is also a photocatalyst under UV light,but the photocatalytic effect only exists in the anatase phase. Asuperhydrophilic surface can contact water with an angle of less than5°. The superhydrophilic effect of Ti_(x)O_(y) is larger for nano-porousstructure, e.g., meso-porous structure (that with pore diameters between20 and 500 angstroms) due to the enlarged surface area (Yu et al., J.Photochem. Photobiol. A, 148:331-39, 2002) and micro-porous structure.Thus, exposure of hydrophobic Ti_(x)O_(y) coating 16 to UV light source30 (e.g., 365 nm, 5 mWcm⁻²) will switch the material back tosuperhydrophilic.

The source of UV light 30 for illuminating stent 10 bearing Ti_(x)O_(y)coating 16 can be, e.g., fibers coupled to high-power diode lasers. Thefibers can be fitted with diffusers that allow sideways radiation. Whenfibers or plastic rods or sheets are notched, light is reflected outfrom the opposite side of the material. Light uniformity is achieved byincreasing the notch depth and frequency, as the distance from the lightsource increases. Rotating this fiber inside stent 10 can provideuniform illumination in all directions. Instead of rotating the fiber, athreaded notch can be generated that will illuminate all directionswithout the need for rotation. Fibers can be obtained from, e.g.,polyMicro (www.polymicro.com). Silica fibers offer good UV transmission.The fibers can be, e.g., about 600 μm to about 2 mm in diameter.

As discussed, placing stent 10 coated with hydrophilic, e.g.,superhydrophilic, Ti_(x)O_(y), e.g., superhydrophilic TiO₂, in the darkwill turn Ti_(x)O_(y) coating 16 hydrophobic. In some embodiments,however, it may be desirable to store (e.g., in the dark, e.g., inpackaging) stents coated with hydrophilic, e.g., superhydrophilicTi_(x)O_(y), without its turning hydrophobic. Reversal fromsuperhydrophilic to hydrophobic surface can be prevented by using anano-porous (inverse-opal) structure of Ti_(x)O_(y) Gu, App. Phys. Lett.85(21):5067-69, 2004.

In one embodiment, a layer of organic compound, e.g., alkyl silane, arylsilane and/or fluoroalkyl silane, can be deposited over the hydrophobicTi_(x)O_(y). For example, a layer of octadecylsilane oroctadecylphosphonic acid over the hydrophobic Ti_(x)O_(y) coating 16 canenhance the superhydrophobic state and stability of coating 16. Balauret al., Electrochem. Communic. 7:1066-70, 2005. Coating 16 in thisembodiment can be turned hydrophilic, e.g., superhydrophilic, by UVlight illumination, as desired.

Stent 10 can include (e.g., be manufactured from) metallic materials,such as stainless steel (e.g., 316L, BioDur® 108 (UNS S29108), and 304Lstainless steel, and an alloy including stainless steel and 5-60% byweight of one or more radiopaque elements (e.g., Pt, Ir, Au, W) (PERSS®)as described in US-2003-0018380-A1, US-2002-0144757-A1, andUS-2003-0077200-A1), Nitinol (a nickel-titanium alloy), cobalt alloyssuch as Elgiloy, L605 alloys, MP35N, titanium, titanium alloys (e.g.,Ti-6Al-4V, Ti-50Ta, Ti-10Ir), platinum, platinum alloys, niobium,niobium alloys (e.g., Nb-1Zr) Co-28Cr-6Mo, tantalum, and tantalumalloys. Other examples of materials are described in commonly assignedU.S. application Ser. No. 10/672,891, filed Sep. 26, 2003; and U.S.application Ser. No. 11/035,316, filed Jan. 3, 2005. Other materialsinclude elastic biocompatible metal such as a superelastic orpseudo-elastic metal alloy, as described, for example, in Schetsky, L.McDonald, “Shape Memory Alloys”, Encyclopedia of Chemical Technology(3rd ed.), John Wiley & Sons, 1982, vol. 20. pp. 726-736; and commonlyassigned U.S. application Ser. No. 10/346,487, filed Jan. 17, 2003.

In some embodiments, materials for manufacturing stent 10 include one ormore materials that enhance visibility by MRI. Examples of MRI materialsinclude non-ferrous metals (e.g., copper, silver, platinum, or gold) andnon-ferrous metal-alloys containing superparamagnetic elements (e.g.,dysprosium or gadolinium) such as terbium-dysprosium, dysprosium, andgadolinium. Alternatively or additionally, stent 10 can include one ormore materials having low magnetic susceptibility to reduce magneticsusceptibility artifacts, which during imaging can interfere withimaging of tissue, e.g., adjacent to and/or surrounding the stent. Lowmagnetic susceptibility materials include those described above, such astantalum, platinum, titanium, niobium, copper, and alloys containingthese elements.

Stent 10 can be of a desired shape and size (e.g., coronary stents,aortic stents, peripheral vascular stents, gastrointestinal stents,urology stents, and neurology stents). Depending on the application,stent 10 can have a diameter of between, e.g., about 1 mm to about 46mm. In certain embodiments, a coronary stent can have an expandeddiameter of from about 2 mm to about 6 mm. In some embodiments, aperipheral stent can have an expanded diameter of from about 5 mm toabout 24 mm. In certain embodiments, a gastrointestinal and/or urologystent can have an expanded diameter of from about 6 mm to about 30 mm.In some embodiments, a neurology stent can have an expanded diameter offrom about 1 mm to about 12 mm. An abdominal aortic aneurysm (AAA) stentand a thoracic aortic aneurysm (TAA) stent can have a diameter fromabout 20 mm to about 46 mm. Stent 10 can be balloon-expandable,self-expandable, or a combination of both (e.g., U.S. Pat. No.5,366,504).

Stent 10 can include a releasable biomolecule, e.g., a therapeuticagent, drug, or a pharmaceutically active compound, such as described inU.S. Pat. No. 5,674,242, U.S. application Ser. No. 09/895,415, filedJul. 2, 2001, and U.S. application Ser. No. 10/232,265, filed Aug. 30,2002. The therapeutic agents, drugs, or pharmaceutically activecompounds can include, for example, anti-proliferative agents,anti-thrombogenic agents, antioxidants, anti-inflammatory agents,immunosuppressive compounds, anesthetic agents, anti-coagulants, andantibiotics. Specific examples of such biomolecules include paclitaxel,sirolimus, everolimus, zotarolimus, picrolimus and dexamethasone.

A number of embodiments have been described. Nevertheless, it will beunderstood that various modifications may be made without departing fromthe spirit and scope of the disclosure. Accordingly, other embodimentsare within the scope of the following claims.

What is claimed is:
 1. A medical device comprising: an elongated tubularstructure having an inner luminal wall surface, an outer abluminal wallsurface, and side wall surfaces extending therebetween, a first coatingon at least one or more regions of the luminal wall surface and/or theside wall surfaces comprising a material comprising titanium (+y) oxide(−x), a second coating on at least one or more regions of the abluminalwall surface comprising the material comprising the titanium (+y) oxide(−x), the material in one of the first coating and the second coatingbeing hydrophobic and the one of the first coating and the secondcoating being hydrophobic, and the material in another of the firstcoating and the second coating being hydrophilic and the other one ofthe first coating and the second coating being hydrophilic, and a layerof organic compound over the first and second coatings.
 2. The medicaldevice of claim 1, wherein the first coating is hydrophilic and thesecond coating is hydrophobic.
 3. The medical device of claim 2, whereinthe first coating is superhydrophilic.
 4. The medical device of claim 2,wherein the second coating further comprises a biomolecule and apolymer.
 5. The medical device of claim 1, wherein the first coating ishydrophobic and the second coating is hydrophilic.
 6. The medical deviceof claim 5, wherein the second coating is superhydrophilic.
 7. Themedical device of claim 1, wherein the first coating covers the luminalwall surface.
 8. The medical device of claim 5 or claim 7, wherein thefirst coating further covers the side wall surfaces.
 9. The medicaldevice of claim 1, wherein the second coating covers the abluminal wallsurface.
 10. The medical device of claim 1, wherein the second coatingfurther comprises a biomolecule.
 11. The medical device of claim 1,wherein the first coating further comprises a biomolecule.
 12. Themedical device of claim 11, wherein the first coating further comprisesa polymer.
 13. The medical device of claim 1, wherein the first coatingand the second coating comprise phosphorus.
 14. The medical device ofclaim 1, wherein one of the first coating and the second coating isporous.
 15. The medical device of claim 14, wherein another of the firstcoating and the second coating is smooth.
 16. The medical device ofclaim 14 further comprising biomolecules in pores of the one of thefirst coating and the second coating.
 17. The medical device of claim 1,wherein the material comprises a crystal.
 18. The medical device ofclaim 1, wherein the material is photoactive.
 19. The medical device ofclaim 1, wherein the material in a first selectable state is hydrophilicand the material in a second selectable state is hydrophobic.
 20. Themedical device of claim 19, wherein the material is selected between thefirst state and the second state by exposure to UV light.
 21. Themedical device of claim 19, wherein the material is selected between thefirst state and the second state by wet-rubbing.